Polysaccharide material for direct compression

ABSTRACT

This invention relates to a method of using compressible polysaccharides having a tap density of less than 0.4 g/ml as a filler/binder for tablets prepared by direct compression, excipient blends including said polysaccharides, a method of tableting an active ingredient therein from the excipient blends and the tablets produced therefrom. More particularly, this invention relates to the use of low-density starches as binders for tablets prepared by direct compression, excipient blends, and methods of tableting an active ingredient therein from such starches. Further, this invention describes a starch-based excipient composition having a tap density of less than 0.4 g/ml, which has excellent moisture resistance.

This application is a regular application based on the priority ofprovisional applications, U.S. Ser. Nos. 60/233,210 and 60/200,858,filed Sep. 15, 2000 and May 1, 2000, respectively.

FIELD OF THE INVENTION

This invention relates to a method of using compressible polysaccharideshaving a tap density of less than 0.4 g/ml as a filler/binder fortablets prepared by direct compression, excipient blends including saidpolysaccharides, a method of tableting an active ingredient therein fromthe excipient blends and the tablets produced therefrom. Moreparticularly, this invention relates to the use of low-density starchesas binders for tablets prepared by direct compression, excipient blends,and methods of tableting an active ingredient therein from suchstarches. Further, this invention describes a starch-based excipientcomposition having a tap density of less than 0.4 g/ml, which hasexcellent moisture resistance.

BACKGROUND OF THE INVENTION

Direct compression is a process by which a powder blend of an activeingredient, such as a drug, and a suitable excipient and/or filler,which is capable of flowing uniformly into a die cavity, are compresseddirectly into an acceptable tablet. The advantages of direct compressioninclude limiting exposure of the active material to moisture and/orheat, and long-term physical and chemical stability. Direct compressionrequires only two steps, mixing the dry ingredients and compressing themixture into a tablet, and hence it is the most preferred and economicalmethod of tableting.

The direct compression process has a number of limitations dependentupon the compactibility, particle size, crystallinity, polymorphism,flowability and density of the excipient as well as the activeingredient. In particular, tablets containing a high dose of an activeingredient which has poor compactibility ordinarily cannot be preparedby direct compression because filler/binders have a limited dilutionpotential. Thus, one of the most important properties of a filler/binderis high compactability which ensures that the compacted mass will remainbonded after the release of the compaction pressure.

It is common to use a combination of two or more filler/binders in orderto obtain a mixture with adequate compactibility, stability, and cost.Only a few excipients can be compressed directly into tablets withoutphysical modification.

Typical direct compression excipients or filler/binders includemicrocrystalline cellulose, specialty compressible sugars, modifiedcalcium salts, lactose, starches, and dextrose. Of these,microcrystalline cellulose (“MCC”) is often the binder of choice.However, MCC has inherent flow problems and is very expensive. Otherfillers/binders include physically modified calcium phosphate (di- ortribasic) and specialty compressible sugars, but each filler/binder hasits limitations. The calcium salts do not allow for the preparation oftablets with a high level of active ingredient, tend to undesirablyalter behavior during prolonged storage and generally require the use ofdisintegrants. The use of sugars (usually sucrose) present a darkeningproblem, tend to change tablet crushability with age, and have chemicalincompatibility with some drugs. Lactose has limited binding propertiesand undesirably darkens in the presence of amino substituted drugs.Specialty mannitol and sorbitol compounds have properties similar tosugars, but have limited application, and are used primarily to providechewable tablets.

Starches and their derivatives have been used as excipients in drugproducts functioning as disintegrants, diluents and binders. Bolhuis,Gerard K. and Chowhan, Zak T., “Materials for Direct Compression” inPharmaceutical Powder Compaction Technology, Alderborn, 9 & NystromEditors, Vol. 71, Chapter 14, 419-500, Marcer Decker, N.Y. Inparticular, U.S. Pat. Nos. 3,622,677 and 4,072,535 issued to R. W. Shortet al. Report that physically modified, partially gelatinized, andpregelatinized starches are useful as binder-disintegrants for directcompression tableting. The modification, which is carried out by passingthe starch through closely spaced steel rollers with or without the useof supplemental thermal energy, disrupts and fractures at least some ofthe granules and results in a mixture of birefringent andnon-birefringent granules and fragments, as well as completelysolubilized starch (typically about 10-20%). The compacted mass isground and classified into desired particle size fractions. Theresulting starch has limited direct compression binding ability, and theuse of an auxiliary binder is often required.

U.S. Pat. No. 4,384,005 issued May 17, 1983 to D. R. McSweeney et al.,describes the use of certain hydrolyzed starches as “melting pointelevators” in a hybrid wet granulation-direct compression tabletingprocess for preparing nonfriable, rapidly water-dispersable tablets forsweetened or unsweetened beverage tablets. The inclusion of a meltingpoint elevator raises the melting point of the mixture so that thetablets made therefrom do not soften, melt or form a hard core duringdrying and compression.

Solubilized fractionated starches described in U.S. Pat. No. 3,490,742issued Jan. 20, 1970 to G. K. Nichols, such as non-granular amylose, arealso reportedly useful as binder-disintegrants in direct compressiontableting processes. The amylose fraction is non-granular because thestarch from which it is derived is totally solubilized in order to freethe amylose. This material is prepared by gelatinizing the starch. Thenhigh molecular weight (long chain) amylose is fractioned from thegelatinized starch in water at elevated temperatures. In order tofunction as a binder, such a starch must contain at least 50% of thenative (e.g., long chain) amylose which was present in the starch.

U.S. Pat. No. 4,551,177 issued Nov. 5, 1985 to Trubiano, et al.discloses a compressible starch, useful as a binder for tablets preparedby direct compression. This starch consists of a free-flowingcompressible powder derived from a cold-water-insoluble, granularstarch. The granular starch is prepared by treatment with an acid,alkali, and/or alpha-amylase enzyme at a temperature below thegelatinization temperature which results in weakened granules havingless dense interiors and disrupted surfaces. Likewise, U.S. Pat. No.5,468,286 issued Nov. 21, 1995 to C. W. Chiu et al. describesenzymatically debranched starches which are also useful as directcompression binders. Both products are substantially crystalline, haverelatively high densities and have low dilution potential compared toother binders used in the industry.

Low-density polymers, including polysaccharides, are known to be usefulin the preparation of cosmetic or pharmaceutical compositions. Suchcompositions are disclosed in European Patent App. No. 659,403 wherein alow-bulk density polysaccharide is used as a carrier for an adsorbed oilor oil soluble substance. In addition, U.S. Pat. No. 4,232,052 issuedNov. 4, 1980 to B. H. Nappen describes a combination of a low-bulkdensity starch and a grinding agent which forms a carrier suitable foradsorbing high fat foodstuffs. These carriers may be incorporated asadjuvants in processed foodstuffs, tablets, or powders.

Unlike other starches used in direct compression binding, it has beendiscovered that the low-density polysaccharides of the present inventionhave unexpectedly excellent compaction properties resulting in tabletcrushing strengths comparable to or better than binders currentlypreferred in the pharmaceutical industry. Thus, the low-densitypolysaccharides of the current invention advantageously providebinder/filler utility as tablet excipients in direct compressionapplications.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates that the crushing strength of tablets composed of 25%low-density starch and 75% Dibasic Calcium Phosphate (“DCP”) increasesas the density of the starch used to prepare the tablets decreases.

FIG. 2 illustrates that tablets prepared from the low-density starchesof this invention as a 20% binder for a poorly compressible activeingredient (ascorbic acid) exceed or are equal to the crushing strengthof a tablet using 20% MCC as the binder.

FIG. 3 illustrates that the crushing strength of tablets formulated with5% of low-density starch form harder tablets that those formulatedwithout such starch.

FIG. 4 illustrates that the increase in the mass fraction of the lowdensity starch of the tablet reduces the compression force needed toproduce tablets having a crushing strength of 98N.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to a method of using compressible polysaccharideshaving a tap density of less than 0.4 g/ml as a filler/binder fortablets prepared by direct compression, excipient blends including saidpolysaccharides, a method of tableting an active ingredient therein fromthe excipient blends and the tablets produced therefrom. Moreparticularly, this invention relates to the use of low-density starchesas binders for tablets prepared by direct compression, excipient blends,and methods of tableting an active ingredient therein from suchstarches. Further, this invention describes a starch-based excipientcomposition having a tap density of less than 0.4 g/ml, which hasexcellent moisture resistance.

The base material for the polysaccharides of this invention can bederived from starches, including the enzymatic, chemical, or heatdegradation products of starch, such as dextrins. Also included as basematerials are gums, such as gum arabic, alginates, pectinate,carrageenans and cellulosics. As used herein, the term “polysaccharide”may include more than one base material.

All starches and flours (hereinafter “starch”) may be suitable for useas base materials herein and may be derived from any native source. Anative starch as used herein, is one as it is found in nature. Alsosuitable are starches derived from a plant obtained by standard breedingtechniques including crossbreeding, translocation, inversion,transformation or any other method of gene or chromosome engineering toinclude variations thereof. In addition, starch derived from a plantgrown from artificial mutations and variations of the above genericcomposition, which may be produced by known standard methods of mutationbreeding, are also suitable herein. Typical sources for the starches arecereals, tubers, roots, legumes and fruits. The nature source can becorn, pea potato, sweet potato, banana, barley, wheat rice, sago,amaranth, tapioca, arrowroot, canna, sorghum, and waxy or high amylosevarieties thereof. As used herein, the term “waxy” is intended toinclude a starch containing at least about 95% by weight amylopectin andthe term “high amylose” is intended to include a starch containing atleast about 40% by weight amylose. The preferred starch is corn, waxycorn, high amylose corn, potato, tapioca, rice, wheat, sago, or waxysorghum starch. The more particularly preferred starch is waxy corn andtapioca dextrin and blends thereof.

Conversion products derived from any of the starches, including fluidityor thin-boiling starches prepared by oxidation, enzyme conversion, acidhydrolysis, heat and or acid dextrinization, thermal and or shearedproducts may also be useful herein. A particularly preferred starchdextrin is tapioca dextrin.

Chemically modified polysaccharides, particularly starches, are alsointended to be included as the base material and include, withoutlimitation, those which have been crosslinked, acetylated andorganically esterified, hydroxyethylated and hydroxypropylated,phosphorylated and inorganically esterified, cationic, anionic,nonionic, and zwitterionic, and succinate and substituted succinatederivatives thereof. Such modifications are known in the art (seeModified Starches; Properties and Uses, Ed. Wurzburg, CRC Press, Inc.,Florida (1986)). Particularly useful are charged based materials; thatis those which are cationic, anionic, or zwitterionic.

Physically modified polysaccharides, such as the thermally-inhibitedstarches described in the family of patents represented by WO 95/04082,may also be suitable for use herein. Also suitable as base materials arepregelatinized starches which are known in the art and disclosed in U.S.Pat. Nos. 4,465,702, 5,037,929, 5,131,953, and 5,149,799. Conventionalprocedures for pregelatinizing starch are also known to those skilled inthe art and described, for example, in Chapter XXII—“Production and Useof Pregelatinized Starch”, Starch: Chemistry and Technology, Vol.III—Industrial Aspects, R. L. Whistler and E. F. Paschall, Editors,Academic Press, New York, 1967.

Methods for producing low-density starches are known in the art. Themethods disclosed herein are examples only, and are not intended to beexclusive means of preparing the low-density starches of the presentinvention. A first method for preparing a low-density polysaccharide isdescribed in U.S. Pat. No. 4,232,052, which is incorporated herein byreference. The polysaccharides of this invention may be prepared bysolubilizing the base material in a solvent, adding a blowing agent anddrying the solution.

Solubilizing the base material may be achieved by thermally cooking aslurry of the base material in a solvent, preferably water, and coolingthe resultant dispersion to ambient room temperature. Thermal cookingmay be achieved either by heating the slurry at elevated temperaturesfor about 30 minutes while agitating, or by subjecting the slurry to acontinuous, direct steam injection cooking apparatus.

The blowing agent may be added to the dispersion prior to drying inorder to decrease the tap (and bulk) density of the resultant powders.Tap and bulk density are defined herein, infra. The decrease in densitymay be accomplished by the expansion of the blowing agent within thespray-dried particle. Any blowing agent may be used which is compatiblewith the dispersion components (i.e. polysaccharide and water) andcapable of expanding the resultant spray dried particle. Particularlysuitable blowing agents include, with limitation, carbon dioxide,ammonium salts, and inorganic salts such as carbonates and bicarbonates,more particularly carbonates and bicarbonates such as ammoniumcarbonate, ammonium bicarbonate, sodium carbonate and sodiumbicarbonate.

The blowing agent may be added in any amount desired, dependent upon theblowing agent, the polysaccharide used and the particle tap densitydesired. In general, the blowing agent will be used in an amount of fromabout 1 to about 100%, particularly from about 2 to about 70%, moreparticularly from about 2 to about 50%, by weight of the starch.

Other drying parameters may include, but are not limited to alterationof nozzle size and configuration of the spray drying apparatus,variation of air, steam or fluid pressure, variation of feed rate,amount of starch solids, inlet temperature and vacuum pressure.

The resulting dried material will be in the form of particles containingan open hollow cavity as disclosed by electron beam magnification. Thedensity and particle size will be dependent on the polysaccharide used,solids content of the starting solution, blowing agent concentration andthe particular drying method used. Tap densities in the range of betweenabout 0.05 to about 0.4 g/ml can be obtained depending upon the solidsconcentration of the solubilized base, blowing agent and dryingparameters. Tap densities of less than about 0.05 g/ml can be obtainedby using a low solids solubilized base solution and a high concentrationof blowing agent.

A second method of preparing the low-density starches of this inventioninvolves allowing a dispersed starch to precipitate in dehydratingmedia. This may be achieved by thermally cooking a slurry of the basestarch having a solids content of from about 10% to about 35% andcooling the dispersion to ambient room temperature. Thermal cooking canbe achieved either by heating the slurry to temperatures of above thegelatinization temperature of the starch for about 30 minutes whileagitating, or by subjecting the slurry to a continuous, direct steaminjection cooking apparatus.

The resultant dispersed starch is then introduced into a dehydratingmedium with mechanical agitation. The starch precipitates, is filteredout of solution, washed with additional dehydrating medium and dried.The preferred dehydrating medium is an alcohol, particularly methanol.Filtration may be accomplished under vacuum, and drying may beaccomplished via a variety of techniques known in the art including airdrying, spray drying or drying in a dessicator. Optionally, theresultant starch solid may be further dried in a forced draft. Inaddition, the starch solid may optionally be sieved, or further groundto achieve the desired particle size. Starches produced via thistechnique have a tap density of below about 0.4 g/ml.

A third method of preparing the low-density starches of this inventionmay be achieved by introducing the dispersed starch produced by thesecond method with shear into a saturated aqueous solution of a salt,such as magnesium sulfate. The rate of the addition of the dispersedstarch is adjusted so that the jacketed temperature of the additionmixture is maintained between about −5° C. to about 85° C. andparticularly between about −5° C. to about 40° C. The resultant starchprecipitate is then filtered out of solution, dried and prepared asdescribed for the second method discussed above. A particularlypreferred drying step for the third method is freeze-drying. The thirdmethod of preparing low-density starches is especially suitable forstarches containing amylose, particularly those starches with an amylosecontent of above about 15%, more particularly above about 50% and mostparticularly above about 65%.

A tap density of 0.4 g/ml correlates to a porosity of 0.70 for thelow-density starches of this invention. Tap density can be correlated toporosity for a given base material for the purpose of estimating thesuitability of such an excipient for binding. However, when comparingthe porosity of different bases via their tap density, the neat densityof the materials must be taken into account. The porosity of such aprocessed powder bed, ε, is related to the tap density, ρ_(tap), of thebinder and the neat density of the base material, ρ_(neat), according toequation (1) below, $\begin{matrix}{ɛ = {\left\lbrack {1 - \left( \frac{\rho_{tap}}{\rho_{neat}} \right)} \right\rbrack.}} & (1)\end{matrix}$

Tap and neat densities, as used herein, are defined herein, infra. Thelow-density starches used as illustrations of this invention all haveneat densities of approximately 1.1 to 1.3 g/ml. A tap density of about0.4 g/ml is thus equivalent to a porosity of about 0.70. Though thedensity of the polysaccharides of this invention are described primarilyas tap densities, one of ordinary skill in the art understands thatpolysaccharides having a porosity of greater than about 0.70 are alsoincluded in the description of this invention.

Although any polysaccharide with a tap density less than about 0.4 g/mlis suitable in the invention, polysaccharides with tap densities of lessthan about 0.2 g/ml are particularly suitable and less than about 0.05g/ml are more particularly suitable. The correlation of low-densitystarches with the increased crushing strength of tablets made from thesestarches via direct compression is illustrated in FIG. 1. For example, astarch having a tap density of 0.030 g/ml exhibited a crushing strengthof about 213 Newtons (“N”) in a tablet containing 25% binding vehicleand 75% dibasic calcium phosphate (DCP), whereas a crushing strength ofonly 27.5 N was demonstrated for a starch having a tap density of 0.440g/ml. A tablet made from 100% DCP has a crushing strength of 19.6 N.

The moisture content of hydrophilic binders is known to affect bindingefficiency at low moisture levels. Prior art compositions, whenformulated into tablets, have shown an unacceptable loss in crushingstrength when exposed to high moisture conditions. Surprisingly, thetablets prepared from the low-density starches of the present invention,did not show the same loss in crushing strength when exposed to the samemoisture conditions. This is particularly true of high molecular weightpolysaccharides. A tablet prepared according to this invention will showless than 30%, and more particularly less than 20% loss in crushingstrength when exposed to 95% relative humidity (“RH”) at 25° C. for 3hours.

The low-density starches of this invention also demonstrate excellentbinding properties as compared to commercial binders used for directcompression, such as MCC. For example, FIG. 2 illustrates that tabletsformulated with the low-density starches of this invention as a 20%binder exceed or are equal to the crushing strength of a tablet preparedusing MCC as a 20% binder.

The low-density polysaccharides of this invention may also be used inconjunction with at least one other excipient in order to manipulateformulation and tablet properties. Additional excipients are oftenstarch powders, which have minimal binding functionality. Typical starchpowders used as excipients include pregelatinized starches, such asStarch 1500® (Colorcon), NATIONAL 78-1551 (National Starch & ChemicalCompany), or corn starch NF (e.g. PURITY® 21 starch—National Starch &Chemical Company). An effective amount of additional excipient isdefined to be the amount of excipient required to confer optimumproperties upon the tablet. Optimum tablet properties may include, butare not limited to, the desirable degree of tablet crushability,friability, disintegration, dissolution and bioavailability.

When necessary, disintegrants may be used. Said optional disintegrantsinclude, without limit, native starches, modified starches, gums,cellulose derivatives, microcrystalline cellulose, clays, effervescentmixtures and enzymes. The amount of binder (or excipient blend), activeingredient, and lubricant, disintegrant and/or diluent, if any, willdepend not only on potency desired but also on the compatibility of thecomponents and the tablet crushability, friability, disintegrability,dissolution, and/or stability of the final tablet. Anti-adherents,glidants, flavors, coloring agents and the like may also be used. Giventhe minimum and preferred characteristics desired in the final product,the tolerable limits on the weight ratio of the components may be easilydetermined by the skilled practitioner.

The active ingredients which may be employed herein constitute allactive ingredients and include pharmacologically active ingredients,including poorly compressible active ingredients such as, for example,ascorbic acid and ibuprofen. The particular nature of the activeingredient is not critical, however, and also includesnon-pharmaceutical active ingredients such as pulverized detergents,dyes, pesticides and food ingredients, including nutritionalsupplements.

EXAMPLES

The following methods and procedures were used to prepare the starchesand blends thereof, and include the preparation and evaluation oftablets containing the compressible starches of this invention. Themethods and procedures are referred to throughout the Examples containedherein.

Methods & Procedures

Measurement of Density

Bulk Density: A known mass of a starch sample was introduced into agraduated 50 ml cylinder, and the volume of the sample determined to thenearest millimeter. The bulk (or poured) density was then obtained bydividing the mass of the solid by the unsettled apparent volume.

Tap Density: The tap density was then obtained by taking the graduatedcylinder containing the known mass of powder used to determine the bulkdensity and placing it in a Erweka SVM 22 Tap Volumeter, or similarapparatus, set for 500 strokes. After tapping was completed, theresulting volume of the material is recorded. The tap density was thendetermined as the weight of the material in the graduated cylinderdivided by the volume of material after tapping is completed.

Neat Density: Neat density was determined by taking a known mass ofstarch sample and grinding it to remove any large scale porosity orstructure from the sample. The ground starch was then placed in a 50 mlvolumetric flask and ethanol added to a total volume of 50 ml. Thevolume and density of the starch is calculated from the volume, weightand density of the ethanol added to the flask.

Blend Preparation

The starches were mixed with the excipient, then mixed in a Turbula(WAB, Type T2F) mixer for 5 minutes. The mixture is sieved through a420-micron sieve and the fraction passing through the screen is used.After mixing, the powders are stored in airtight containers until theyare used.

Tableting Procedures

Procedure 1—Piccola 10-station Tablet Press

The blends were compressed using an instrumented Piccola 10-stationtablet press. One station on the tablet press was fitted with a 12.5millimeter flat-faced punch and corresponding die. The tablet weightswere adjusted to 500 mg and the tablets compressed at 13.9 Mega Pascals(“MPa”) compression force.

Procedure 2—Single Punch Tablet Press (Globepharma Model MTCM-1)

The single station tablet press was fitted with a 12.5 mm punch and acorresponding die. 500 mg of the powder was weighed (1% accuracy) fedinto the die cavity and compressed at 13.9 MPa compression force. Thecompaction time took about two to three seconds.

Crushing Strength Measurements

Crushing strengths were determined for five tablets, prepared accordingto either Procedure 1 or 2, using a Pharmatron (Model 6D) tablet tester.

EXAMPLES

The following examples will illustrate the embodiments of thisinvention. Sample numbers are assigned to materials used asbinders/fillers and represent the binders of the present invention andother commercially known fillers/binder. Tablets formulated from acertain binder/filler are assigned a particular Sample numbercorresponding to the particular binder/filler comprised therein, but donot necessarily correspond to the same tablet formulation. The sameSample number is used to describe the same binder/filler throughout theexamples. If not specified otherwise, all percents are weight percents.

Example 1 Use of a Low-density Starch as a Direct Compression Binder andPreparation Thereof Via Using a Latent Gas (Method One)

The use of the low-density starches of the present invention as directcompression binders was evaluated by making 100% low-density starchtablets and determining their tablet crushing strengths.

Low-density waxy corn starch (Sample 1) was prepared by jet cooking a17.86% by weight slurry of waxy corn starch at 165° C., cooling themixture to 60° C. and adjusting the solids to 8% by weight. This wasfollowed by the addition of 50% ammonium carbonate on weight of starch.The resultant solution was then spray dried in a Niro spray drier withan inlet temperature set at 320° C. using a conventional ¼ J nozzle withair atomization at 620 kPa. The collected starch had a tap density of0.030 g/ml (Sample 1).

The low-density starch thus prepared was evaluated as a directcompression binder at 100% of tablet formulation by comparison withother commercially available filler/binders including Starch 1500®(Colorcon, Lot 8090171), Microcrystalline Cellulose, (Avicel® PH-102 NF,FMC Lot #2813) and dibasic calcium phosphate (Spectrum, Lot OS0311),Tablets composed of 100% of each binder were prepared according toProcedure land their crushing strength was measured. The data isreported in Table 1.

TABLE 1 Average Description of Crushing Tapped binder/filler Strength(N) Density (g/ml) Sample 1 >453.1* 0.030 Partially pregelatinizedstarch 31.4 0.740 Microcrystalline cellulose (MCC) 341.3 — 100% Dibasiccalcium phosphate 19.6 — (DCP) *Machine limit is 453 N.

The data demonstrated that the low-density starch of the presentinvention provided tablets with a higher crushing strength than othercommercially available binders, when used at 100%. In particular, thetablets of this invention had significantly higher crushing strengththan tablets prepared from other starch-based filler/binders such astablet prepared from Starch 1500®. In addition, the crushing strength ofthe tablets of this invention were superior to that of conventionalcommercially available binders such as MCC or DCP.

Example 2 Use of a Low-density Amorphous Starch as a Direct CompressionBinder in Presence of Other Excipients

The low-density starches of the present invention were blended withthree common excipients used in the pharmaceutical industry in directcompression applications to demonstrate that their binding ability isindependent of excipient.

The low-density waxy corn starch prepared according to Example 1(Sample 1) was blended with lactose anhydrous (Quest, Lot MRP 833555),dibasic calcium phosphate, (Spectrum, Lot OS0311), and Starch 1500®,(Colorcon, Lot 8090171) to afford 5% w/w starch powder blends. Tabletswere prepared from each powder blend according to Procedure 1. Thecrushing strength data for the three excipient blends as well as thecrushing strength of placebo tablets prepared from the excipient aloneare reported in Table 2.

TABLE 2 Mass Fraction (w/w) Sample 1 Crushing Excipient (tap density =0.030 g/ml) Strength (N) Dibasic calcium 0.00 — phosphate 5.01 42.2Lactose 0.00 55.9 Anhydrous 5.01 82.4 Starch 1500 ® 0.00 11.8 5.00 28.4

As the data in Table 2 illustrates, the crushing strength of the tabletswas significantly enhanced by the 5% w/w inclusion of the low-densitystarch (Sample 1) demonstrating the potential of low-density starches tooperate as effective binders in excipient blends for direct compressionapplications.

Example 3 Effect of Density on the Crushing Strength of Placebo Tablets

This example illustrates how the crushing strength of a tablet may beincreased by lowering the density of the low-density starch which isbeing used in an excipient blend. This example also illustrates thattablet crushing strength is independent of the type of starch base usedto produce the low-density starch.

Four low-density waxy corn starches were prepared using the methoddescribed in Example 1, with 50% ammonium carbonate on weight of starch(Sample 1), 37.5% (Sample 2), 25% (Sample 3) and 12.5% (Sample 4) toprovide low-density starches with a range of densities. For comparisonpurposes, a low-density starch also prepared from a drum dried waxy cornstarch (Sample 5) with a tap density greater than 0.4 g/ml and tapiocadextrin (Sample 6, preparation of the starch based described in U.S.Pat. No. 4,232,052). Finally, a low-density starch blend was preparedfrom a 50:50 w/w mixture of Sample 5 and Sample 6 (Sample 7).

These low-density starches were then sieved on a Tyler Rotap SieveShaker for 10 minutes to collect the fraction having a 75-250 micrometerparticle size. A 25% blend of the above materials were made with dibasiccalcium phosphate (Spectrum, Lot OS0311), tabletted according toProcedure 2 and evaluated for crushing strength. The data is presentedin Table 3.

TABLE 3 Mass Fraction Average Crushing Sample # Of Sample Strength (N)TAP Density (g/ml) Sample 10 * 19.6 — Sample 1 25.00% 212.8 0.030 Sample2 25.00% 149.1 0.045 Sample 3 25.00% 136.3 0.106 Sample 4 25.00% 100.00.155 Sample 5 25.00% 27.5 0.440 Sample 6 25.00% 174.6 0.103 Sample 725.00% 78.5 0.20  *Tablet is 100% DCP

As is demonstrated in Table 3, the lower the tap density of the starchused in the blends, the higher the crushing strength of thecorresponding tablet. The starch (Sample 5) with a tap density above 0.4g/ml did not perform as well as any of the lower density starches orexcipient blends containing low-density starches. In addition, tabletsprepared from low-density tapioca dextrin had a similar crushingstrength to the waxy corn low-density starch of similar tap density.Accordingly, the crushing strength of a tablet formulated from the abovematerials was independent of the type of material used. In conclusion,the tap density of the starches, or blend of starches, was the criticalfactor which conferred crushing strength upon tablets preparedtherefrom.

Example 4 Effect of the Density of the Starch on the Crushing Strengthof Placebo Tablets—Comparison With Commercial Excipients

This example defines the upper limit of starch tap density which confersoptimum crushing strength on tablets prepared from the starch of thisinvention.

The starches evaluated as tablet binders in Example 3 were included inthis Example. In addition, Starch 1500® (Sample 8, Colorcon, Lot8090171) was evaluated as an example of a commonly used filler/binderstarch-based excipient. Microcrystalline cellulose, MCC, (Sample 9,Avicel® PH-102 NF, FMC Lot #2813) was also evaluated as a commonly useddirect-compression excipient.

Blends of the above described starches and MCC were made at 25% massfraction with DCP were tabletted according to Procedure 2 and theircrushing strengths measured and reported in Table 4.

TABLE 4 (25% mass fraction binder with DCP) Binder Average CrushingSample # Strength (N) Tap Density (g/ml) 1 212.8 0.030 2 149.1 0.045 3136.3 0.106 4 100.0 0.155 5 27.5 0.440 6 174.9 0.103 7 78.5 0.200 8 17.70.740 9 54.9 —

Tables incorporating the low-density starch blends of the presentinvention, having tap densities of less than 0.4 g/ml, preferably lessthan 0.2 g/ml and more preferably below 0.1 g/ml, showed significantimprovement in crushing strength as compared to industry standards (i.e.Samples 8 and 9).

Example 5 Dilution Potential of Low-density Starches Used as DirectCompression Excipients—Dilution With Ascorbic Acid

This example illustrates that the low-density starches of this inventioncan be used at a high dilution potential when tabletted with a poorlycompressible drug, ascorbic acid (Changzhou Benchi Pharmaceutical Co,Lot 9909014), as compared to other commonly used direct compressionbinders which have a high dilution potential, such as MCC.

A low-density tapioca dextrin (Sample #6) and a low-density waxy cornstarch (Sample #5), and blends thereof (Sample #7), were formulated withascorbic acid and tabletted according to Procedure 2. Correspondingblends of MCC (Sample #9, Avicel® PH-102 NF, FMC Lot #2813) were alsoformulated with ascorbic acid and tabletted according to Procedure 2.The crushing strength of the tablets was measured and the data reportedin Table 5.

TABLE 5 Sample %: Average Crushing Ascorbic Acid % Sample # Strength (N)Tap Density (g/ml) 20%:80% 6 112.8 0.103 5 8.8 0.440 7 48.1 0.200 9 33.3— 10%:90% 6 34.3 0.103 0:100% Could not be compressed at 13.9 MPa

Tablets prepared with 20% binder prepared from the starches or dextrinshaving a tap density below 0.4 g/ml, and blends thereof, had greatercrushing strength than tablets prepared with 20% MCC (w/w %), the mostcommonly used direct compression binder in the pharmaceutical industry.The lowest density starch used in this study (Sample 6, 0.103 g/ml)produced tablets with more than three times the crushing strength oftablets prepared with the same binder percentage. A tablet prepared withonly 10% binder prepared from Sample 6 had comparable crushing strengthto a tablet prepared with 20% MCC.

Example 6 The Effect of Density and Concentration of the Low-densityStarch on the Crushing Strength of Tablets Containing an ActivePrinciple

This example illustrates the effect of the density of the starches ofthe present invention as well as starch concentration on the crushingstrengths of tablets containing an active principle or other commercialexcipient.

Ibuprofen (Lot #C699100, H&A industrial Inc, Ontario, Canada) and Starch1500® were mixed with the low-density starches of the present inventionto yield a final composition containing 50% active and either 0, 5, or10% of the low-density starch. The results are reported in FIG. 1.

FIG. 3 shows that the crushing strength of tablets formulated with 5% ofthe low-density starches form harder tablets than tablets formulatedwithout the low-density starch. Higher percentages of the starchesresulted in harder tablets.

Example 7 The Effect of Moisture on the Crushability of Tablets PreparedFrom Low and High Molecular Weight Low-density Starches

This example demonstrates that high molecular weight low-densitystarches, such as native starches, have superior crushing strengthcompared to tablets made from lower molecular weight low-densitystarches, such as dextrins, in high moisture environments.

Tablets containing 25% binder and 75% dibasic calcium phosphate wereformulated using Sample 1 and Sample 6. The formulations were compressedusing Procedure 2 and their crushing strengths measured. Three tabletsof each formulation were placed in an approximately 95% relativehumidity environment at 25° C. for 3 hours (“high humidity conditions”).After removal, the crushing strength was determined. The data istabulated in Table 6.

TABLE 6 Exposure to Average Crushing 95% RH Sample # Strength (N)Molecular Weight Before 1 212.8 High Exposure 6 174.6 Low 7 112.8 High +Low 3 hours After 1 193.2 High Exposure 6 94.1 Low 7 106.9 High + Low

These results indicate that a tablet made from a high molecular weightmaterial (Sample 1) loses only 9.2% of its crushing strength. A Tabletmade from a blend of high and low molecular weight material (Sample 7)loses even less crushing strength, only 5% loss. In contrast, a tabletincluding only lower molecular weight materials (Sample 6), loses morethan 40% of its crushing strength.

Thus, the polysaccharides of this invention, which have a molecularweight higher than tapioca dextrin (Sample 6) and a tap density of lessthan 0.2 g/ml lose less than 25% of their crushing strength under highhumidity conditions.

Example 8 The Effect of Low-density Starch Incorporation on theCompression Force Needed to Make Tablets

This example illustrates the functionality of low-density starch asbinder in tablet formulations.

The low-density starch was evaluated as a binder in lactose and 50:50w/w % lactose/MCC blends. The powder blends of Sample 1 and lactoseand/or MCC were made containing 0, 1, 3, 5, or 10% wt/wt % of thelow-density starch. The force needed to compress the powders intotablets with a crushing strength of 98N (using procedure 2) was measuredand recorded.

As illustrated by FIG. 4, an increase in the mass fraction of thelow-density starch of the tablet reduced the compression force needed toproduce tablets having a crushing strength of 98N. A reduction of therequired compression force is indicative of the binding functionality ofthe low-density starch.

Example 9 The Preparation of Low-density Starch Via AlcoholPrecipitation (Method Two)

This example demonstrates that suitable low-density starches may beprepared by precipitation out of a dehydrating media, such as alcohol,thus obviating the need for a gas or latent gas.

The starch was prepared by slurrying a 10% by mass waxy corn starch inwater, heating the slurry in a boiling water bath for 30 minutes, andcooling the resultant starch solution to room temperature. The starchwas precipitated out by adding the cooled starch solution slowly tomethanol to form a 20% by weight aqueous methanol solution (100 partsstarch cook to 450 parts methanol). The solution was decanted off theprecipitate, an equal volume of fresh solution was added, and the sampleallowed to stand overnight. The starch was recovered by filtration,air-dried, ground and passed through a 240 micron sieve. The resultantstarch product was determined to have a tap density of 0.300 g/ml.

This low-density starch product was blended with dibasic calciumphosphate (DCP) in a ratio of 25:75 by weight blend (starch:DCP) andtabletted according to Procedure 2. The crushing strength of thetabletted blend was 87 N, significantly higher than a correspondingtablet in which the industry standard MCC was substituted for thelow-density starch (crushing strength of only 55 N).

Example 10 The Preparation of Low-density Starch Via Precipitation ofthe Starch From an Aqueous Salt Solution (Method Three)

This example illustrates a third method for preparing the low-densitystarches of the present invention comprising precipitating starch out ofan aqueous salt solution.

The starch was prepared by slurrying dispersed 10% Hylon® VII starch(National Starch & Chemical Co.) in water and heating the slurry in aboiling water bath for 30 minutes. The hot dispersed starch solution wasthen added to a saturated aqueous solution of magnesium sulfate withmechanical shear. The rate of the addition was adjusted to maintain thetemperature of the jacketed solution to about 30° C. over three hours.The agitation was maintained for three hours.

The starch was then filtered out of solution, washed with water,re-slurried in water and freeze-dried to 5.2% moisture by weight. Theresultant starch had a tap density of 0.19 g/ml. The crushing strengthof a tablet formulated from 25% starch and 75% DCP which had beentabletted by Procedure 2 had a crushing strength of 92 N, similar to theother low-density starches of the present invention.

We claim:
 1. A polysaccharide having a tap density of less than about0.05 g/ml.
 2. The polysaccharide of claim 1, wherein the polysaccharideis at least one starch.
 3. The polysaccharide of claim 2 wherein the atleast one starch is selected from the group consisting of corn, waxycorn, high amylose corn, potato, tapioca, rice, sago, wheat or waxysorghum starch.
 4. A polysaccharide having a tap density of less thanabout 0.2 g/ml which, when used in an binding effective amount in atablet, prevents the crushing strength of the tablet from decreasingmore than about a 20% decrease in crushing strength when exposed to 95%relative humidity at 25° C. for 3 hours wherein the crushing strength ismeasured according to Procedures 1 or 2, herein.
 5. The polysaccharideof claim 4, wherein the tap density is less than about 0.1 g/ml.
 6. Thepolysaccharide of claim 4, wherein the polysaccharide is at least onestarch.
 7. A directly compressible tablet comprising a polysaccharidehaving a tap density which has been decreased to less than about 0.4g/ml, and an active agent.
 8. The tablet of claim 7, wherein thepolysaccharide has a tap density is less than about 0.2 g/ml.
 9. Thetablet of claim 7, wherein the polysaccharide has a tap density is lessthan about 0.05 g/ml.
 10. The tablet of claim 7, wherein thepolysaccharide is at least one starch.
 11. The polysaccharide of claim10 wherein the at least one starch is selected from the group consistingof corn, waxy corn, high amylose corn, potato, tapioca, rice, sago,wheat or waxy sorghum starch.
 12. The tablet of claim 7, wherein the atleast one starch is a blend of tapioca dextrin and pregelatinized waxycorn.
 13. The tablet of claim 7, wherein the tablet is a pharmaceuticaltablet.
 14. The tablet of claim 7, wherein the active agent is poorlydirectly compressible.
 15. A directly compressible tablet comprising apolysaccharide, an excipient, and an active agent, wherein a mixture ofthe polysaccharide and the excipient has a tap density of less thanabout 0.4 g/ml.
 16. The tablet of claim 15, wherein the tap density ofthe mixture is less than about 0.2 g/ml.
 17. The tablet of claim 15,wherein the polysaccharide is at least one starch.
 18. The tablet ofclaim 17, wherein at least one starch is a blend of tapioca dextrin andpregelatinized waxy cornstarch.
 19. A method of making a tabletcomprising directly compressing a polysaccharide having a tap density ofless than about 0.4 g/ml and/or a porosity of no more than about 0.7,and an active agent.
 20. The method of claim 19, wherein thepolysaccharide is a blend of tapioca dextrin and pregelatinized waxycorn.
 21. A method of making a tablet comprising directly compressing apolysaccharide, an excipient, and an active agent, wherein a mixture ofthe polysaccharide and the excipient has a tap density of less thanabout 0.4 g/ml.
 22. The method of claim 21, wherein the polysaccharideis a blend of tapioca dextrin and pregelatinized waxy corn starch.